DRUG RECORD

FAMOTIDINE

Introduction

Famotidine is a histamine type 2 receptor antagonist (H2 blocker) which is commonly used for treatment of acid-peptic disease and heartburn. Famotidine has been linked to rare instances of clinically apparent acute liver injury.

Background

Famotidine (fam oh' ti deen) was the third H2 blocker introduced into clinical practice in the United States and is a commonly used agent for treatment of duodenal and gastric ulcer and gastroesophageal reflux disease. The H2 blockers are specific antagonists of the histamine type 2 receptor, which is found on the basolateral (antiluminal) membrane of gastric parietal cells. The binding of famotidine to the H2 receptor results in inhibition of acid production and secretion, and improvement in symptoms and signs of acid-peptic disease. The H2 blockers inhibit an early, “upstream” step in gastric acid production and are less potent that the proton pump inhibitors, which inhibit the final common step in acid secretion. Nevertheless, the H2 blockers inhibit 24 hour gastric acid production by about 70% and are most effective in blocking basal and nocturnal acid production. Famotidine was first approved for use in the United States in 1986 and more than 3 million prescriptions for it are filled yearly. Famotidine is now available both by prescription and over-the-counter. The listed indications for famotidine are duodenal and gastric ulcer disease, gastroesophageal reflux and prevention of stress ulcers. Famotidine is available in tablets of 20 and 40 mg in several generic forms and in parenteral forms under the brand name Pepcid. Over-the-counter formulations are typically gelcaps or tablets of 10 or 20 mg. Liquid solutions are also available for intravenous use. The typical recommended dose for therapy of peptic ulcer disease in adults is 40 mg once daily for 4 to 8 weeks and maintenance therapy of 20 mg daily. Lower, chronic and intermittent doses of famotidine are used for therapy of heartburn and indigestion. Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches. Famotidine is metabolized by the hepatic cytochrome P450 system, but has minimal inhibitory effects on the metabolism of other drugs, making it less likely to cause drug-drug interactions than cimetidine.

Hepatotoxicity

Chronic therapy with famotidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations are usually asymptomatic and transient, and may resolve without dose modification. Rare instances of clinically apparent liver injury have been reported in patients receiving famotidine, but few cases have been reported and clinical characteristics in published cases have varied in the time to onset and pattern of injury. Onset has ranged from 1 to 14 weeks and serum enzyme pattern has typically been hepatocellular. The injury resolves within 4 to 12 weeks of stopping famotidine. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation.

Mechanism of Injury

Famotidine is metabolized by the microsomal P450 drug metabolizing enzymes and injury may be the result of its activation to a toxic intermediate.

Outcome and Management

The hepatic injury caused by famotidine is usually rapidly reversible with stopping the medication (Case 1). Famotidine has not been definitively linked to cases of acute liver failure, chronic hepatitis, prolonged cholestasis or vanishing bile duct syndrome. The results of rechallenge have not been reported. There appears to be cross reactivity in hepatic injury with cimetidine (Case 2). If acid suppression is required, use of an unrelated proton pump inhibitor is probably prudent for patients with clinically apparent famotidine induced liver injury.

The H2 receptor blockers include cimetidine, famotidine, nizatidine, and ranitidine. Combined references on all four agents are given together after the Overview section on H2 blockers, as well as specific references after each drug. See also the proton pump inhibitors.

A 55 year old man with gastritis and abdominal pain was treated with ranitidine (150 mg twice daily) for 5 days and, when symptoms continued, was switched to famotidine (20 mg twice daily) and sucralfate (1 g four times daily). One week later he developed nausea and jaundice. He denied fever, chills, rash or pruritus. He had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. He had been taking acetaminophen for the previous ten days (625 mg four times daily). On physical examination, he was jaundiced and had tenderness over the liver, but no fever, rash or signs of chronic liver disease. Laboratory results showed elevations in serum bilirubin with moderate elevations in serum ALT and alkaline phosphatase (Table). He tested negative for markers of viral hepatitis (A, B and C) and for autoimmune liver disease. Acetaminophen levels were normal (7 µg/mL: normal therapeutic range 10-20). Abdominal ultrasound showed no gallstones or evidence of biliary obstruction. Famotidine was stopped and he rapidly improved. A liver biopsy was not done. When seen five weeks later, all laboratory tests had returned to normal.

Comment

This patient developed a mild acute hepatitis 1 week after starting famotidine. While he had also been taking moderate doses of acetaminophen (2.5 g per day for 10 days), the pattern of injury was not typical of acetaminophen hepatotoxicity and acetaminophen levels were actually below the therapeutic range and well below the toxic range on admission. The pattern and course of the liver injury was quite typical of idiosyncratic drug induced liver injury and compatible with the type of injury that has been reported with H2 blockers with a short latency (1 week), and a hepatocellular or mixed pattern of liver enzyme elevation. An issue is whether the 5 days of ranitidine may have caused or contributed to the injury and whether there may be cross sensitivity to hepatic injury among the various H2 blockers. Such cross sensitivity has been shown between famotidine and cimetidine (Case 2 below).

A 51 year old woman with symptomatic duodenal ulcer disease was treated with famotidine (40 mg daily), with subsequent improvement in epigastric pain and nausea, but with reappearance of abdominal discomfort followed by dark urine, itching and jaundice starting 3 weeks later. She denied fever or rash or history of drug allergy. She was overweight (BMI = 34.1), but had lost 2.3 kilograms in the previous week. She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. On examination, she was jaundiced and had mild hepatic tenderness but no peripheral signs of chronic liver disease. Laboratory testing showed total serum bilirubin of 5.0 (direct 4.1) mg/dL, ALT 661 U/L, alkaline phosphatase 193 U/L, with normal serum albumin and prothrombin time (Table). Tests for hepatitis A, B and C were negative as were autoantibodies. Ultrasound of the abdomen showed an echogenic liver suggestive of steatosis, but no evidence of biliary obstruction. Famotidine was stopped and omeprazole (20 mg daily) substituted. She improved rapidly and liver tests were normal or near normal five weeks later, at which point cimetidine (800 mg daily) was substituted for omeprazole. One week later she redeveloped abdominal pain and nausea. The dose of cimetidine was increased, but over the next week she developed worsening symptoms and dark urine. Laboratory testing showed rises in serum bilirubin, ALT and alkaline phosphatase similar to those after famotidine therapy and cimetidine was stopped. Repeat evaluation revealed no evidence of viral hepatitis, autoimmune liver disease or biliary obstruction. She improved and was maintained on omeprazole therapy for her acid-peptic disease. In follow up 6 weeks later, liver tests had returned to normal or near-normal levels.

Key Points

Medication:

Famotidine (40 mg daily), cimetidine (800 to 1200 mg daily)

Pattern:

Hepatocellular (R=14)

Severity:

3 (jaundice, hospitalization)

Latency:

3-4 weeks for famotidine, 1-2 weeks for cimetidine

Recovery:

6 weeks

Other medications:

Antacids, occasional acetaminophen, oral contraceptives (many years)

Laboratory Values

Time After Starting

Time After Stopping

ALT (U/L)

Alk P (U/L)

Bilirubin (mg/dL)

Other

0

Famotidine (40 mg/day) started

4 weeks

0

661

193

5.0

Famotidine stopped

5 weeks

1

250

250

1.5

Symptoms resolved

6 weeks

2

120

150

1.0

9 weeks

5

55

Cimetidine started

11 [2] weeks

[0]

590

180

4.4

Cimetidine stopped

[3] weeks

[1] week

430

320

8.2

[4] weeks

[2] weeks

190

210

1.2

[5] weeks

[3] weeks

90

180

[7] weeks

[5] weeks

48

120

1.0

[9] weeks

[7] weeks

44

60

Normal Values*

<35

<150

<1.2

* Some values estimated from Figure 1, and bilirubin levels converted from µmol to mg/dL. Weeks in parentheses represent time after starting and stopping cimetidine.

Comment

This patient appeared to develop a transient and self-limiting acute hepatitis-like injury after both famotidine and cimetidine therapy. The cross reactivity of these two agents was not suspected, based upon the lack of such cross reactivity to hepatic injury between cimetidine and ranitidine. However, in the case shown above, the recurrence was more rapid and perhaps slightly more severe with the “re-exposure” using cimetidine. Typical of H2 receptor blocker induced liver injury was the rapid recovery upon withdrawal. While liver biopsy was not done, in most such instances centrolobular necrosis with inflammation and mild cholestasis is found. This patient may have had mild underlying nonalcoholic fatty liver disease, but this is a common medical condition and unlikely played a role in the clinically apparent liver injury.

Product labeling at DailyMed, National Library of Medicine, NIH

References Last Updated: 21 March 2014

Zimmerman HJ. H2 Receptors antagonists. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 719-20. (Expert review of hepatotoxicity published in 1999 states that cimetidine and ranitidine, despite enormous use, have been implicated in a small number of cases of hepatic injury, 39 for cimetidine, 35 for ranitidine and 1 for famotidine, all cases recovering and signs of hypersensitivity being rare).

Lewis JH. Hepatic effects of drugs used in the treatment of peptic ulcer disease. Am J Gastroenterol 1987; 82: 987-1003. PubMed Citation(Thorough review of hepatotoxicity of antiulcer medications; 10 published cases of hepatotoxicity due to cimetidine and 12 for ranitidine, none fatal and not all convincingly due to the medication; little information available on famotidine or nizatidine).

Howden CW, Tytgat GN. The tolerability and safety profile of famotidine. Clin Ther 1996; 18: 36-54. PubMed Citation(Analysis of safety in 7483 patients in 27 trials of famotidine; side effects were uncommon [<1% for any specific symptom] and no more common than with placebo or comparator agents such as ranitidine; ALT elevations occurred in 2.2% on famotidine, 2.0% on ranitidine and 2.7% on placebo; only 1 patient discontinued famotidine because of elevation of liver tests).

García Rodríguez LA, Ruigómez A, Jick H. A review of epidemiologic research on drug-induced acute liver injury using the general practice research data base in the United Kingdom. Pharmacotherapy 1997; 17: 721-8. PubMed Citation(Combined analysis of 8 epidemiologic studies using the UK General Practice Research Database estimated incidence rates of acute liver injury to be highest for isoniazid and chlorpromazine [4 and 1.3 per 1000 users], intermediate for amoxicillin-clavulanate, cimetidine and ranitidine [2.3, 2.3 and 0.9 per 10,000], and lowest for trimethoprim/ sulfamethoxazole, omeprazole, amoxicillin and nonsteroidals [5.2, 4.3, 3.9 and 3.7 per 100,000]; famotidine not discussed).

Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence,
presentation and outcomes in patients with drug-induced liver injury in the
general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation(In a population
based study of drug induced liver injury from Iceland, 96 cases were identified
over a 2-year period, but none were attributed to famotidine or other antiulcer medications).